The prior art has included numerous methods for preserving or fixing biological tissues, to enable such tissues to be subsequently implanted into mammalian bodies. Examples of the types of biological tissues that have heretofore been utilized for surgical implantation include cardiac valves, vascular tissue, skin, dura mater, pericardium, ligaments and tendons.
The term "grafting" as used herein is defined as the implanting or transplanting of any living tissue or organ (See Dorlands Illustrated Medical Dictionary, 27th Edition, W. B. Saunders Co. 1988). Biological tissues which are grafted into the body of a mammal may be xenogeneic (i.e., a xenograft) or allogeneic (i.e., an allograft). The term "bioprosthesis" defines many types of biological tissues chemically pretreated before implantation (Carpentier--See Ionescu (editor), Biological Tissue in Heart Valve Replacement, Butterworths, 1972). As opposed to a graft, the fate of a bioprosthesis is based upon the stability of the chemically treated biological material and not upon cell viability or host cell ingrowth. Chemical pretreatment includes the "fixing" or tamning of the biological tissue. Such fixing or tanning of the tissue is accomplished by exposing the tissue to one or more chemical compounds capable of cross-linking collagen molecules within the tissue.
Various chemical compounds have been utilized to fix or cross-link biological tissues including formaldehyde, glutaraldehyde, dialdehyde starch, hexamethylene diisocyanate and certain polyepoxy compounds.
In particular, glutaraldehyde has proven to be relatively physiologically inert and suitable for fixing various biological tissues for subsequent surgical implantation (Carpentier, A., J. Thorac. Cardiovasc. Surg. 58:467-68 (1969)). In particular, examples of the types of biological tissues which have heretofore been subjected to glutaraldehyde fixation include porcine bioprosthetic heart valves and bovine pericardial tissues.
Clinical experience has revealed that glutaraldehyde-fixed bioprosthetic tissues may tend to become calcified. Such calcification of glutaraldehyde-fixed bioprosthetic tissues has been reported to occur most predominantly in pediatric patients see, Carpentier et al. and "Continuing Improvements in Valvular Bioprostheses, J. Thorac Cardiovasc. Surg. 83:27-42, 1982. Such calcification is undesirable in that it may result in deterioration of the mechanical properties of the tissue and/or tissue failure. In view of this, surgeons have opted to implant mechanical cardiovascular valves into pediatric patients, rather than to utilize glutaraldehyde-preserved porcine valves. However, pediatric patients who receive mechanical valve implants require long term treatment with anticoagulant medications and such anticoagulation is associated with increased risk of hemorrhage.
The mechanism by which calcification occurs in glutaraldehyde-fixed bioprosthetic tissue has not been fully elucidated. However, factors which have been thought to influence the rate of calcification include:
a) patient's age PA1 b) existing metabolic disorders (i.e., hypercalcemia, diabetes, kidney failure . . . ) PA1 c) dietary factors PA1 d) race PA1 e) infection PA1 f) parenteral calcium administration PA1 g) dehydration PA1 h) distortion/mechanical factors PA1 i) inadequate coagulation therapy during initial period following surgical implantation; and PA1 j) host tissue chemistry
Methods for treating fixed biological tissue so as to inhibit calcification thereof following implantation in a mammalian body tend to substantially increase the usable life of such tissue subsequent to implantation in a mammalian body, thereby mitigating the requirement for subsequent tissue replacement. As those skilled in the art will appreciate, such tissue replacement frequently causes substantial trauma to the patient, occasionally resulting in the patient's death. As such, it is greatly beneficial to be able to either avoid or postpone the need for the replacement of implanted biological tissue.
Various efforts have been undertaken to find ways of mitigating calcification of glutaraldehyde fixed bioprosthetic tissue. Included among these calcification mitigation techniques are the methods described in U.S. Pat. No. 4,885,005 (Nashef et al.) SURFACTANT TREATMENT OF IMPLANTABLE BIOLOGICAL TISSUE TO INHIBIT CALCIFICATION; U.S. Pat. No. 4,648,881 (Carpentier et al.) IMPLANTABLE BIOLOGICAL TISSUE AND PROCESS FOR PREPARATION THEREOF; U.S. Pat. No. 4,976,733 (Girardot) PREVENTION OF PROSTHESIS CALCIFICATION; U.S. Pat. No. 4,120,649 (Schechter) TRANSPLANTS; U.S. Pat. No. 5,002,2566 (Carpentier) CALCIFICATION MITIGATION OF BIOPROSTHETIC IMPLANTS; EP 103947A2 (Pollock et al.) METHOD FOR INHIBITING MINERALIZATION OF NATURAL TISSUE DURING IMPLANTATION; WO84/01879 (Nashef et al.) SURFACTANT TREATMENT OF IMPLANTABLE BIOLOGICAL TISSUE TO INHIBIT CALCIFICATION; U.S. Pat. No. 5,595,571 (Jaffe) BIOLOGICAL MATERIAL PRE-FIXATION TREATMENT; and WO95/11047 (Levy et. al.) METHOD OF MAKING CALCIFICATION-RESISTANT BIOPROSTHETIC TISSUE.
Although some researchers believe that glutaraldehyde actually increases the risk of calcification, it is still the most accepted fixation solution. For example, the Levy patent application noted above utilizes an alcohol treatment for mitigating calcification, in addition to a glutaraldehyde fixation
There is significant research occurring into the extent the mechanisms mentioned above cause calcification. Many processes are believed to mitigate calcification, without their proponents knowing exactly why. Indeed, the Levy patent does not offer a mechanism why alcohol is effective in calcification mitigation, other than it is preferred over aldehydes.
A number of tests are conventionally used to gauge the efficacy of various calcification mitigation treatments. The most reliable test is actual implantation into a living organism, preferably a human. Of course, such host studies are by their nature long-term and the results somewhat skewed by the variations present in each individual host. Researchers are therefore constrained to predict the ultimate calcification mitigation benefits of a particular treatment by using laboratory tests on treated tissue, such as calcium uptake studies. Ultimately, there is a substantial amount of extrapolation from the empirical data of such laboratory tests, and to date there is no one predominant mechanism recognized for mitigating calcification.
There remains a need for the development of new methods for inhibiting or mitigating calcification of chemically fixed biological tissue.